PROJECT SUMMARY/ABSTRACT After obtaining a Ph.D. in Microbiology, I pursued postdoctoral training in gastrointestinal oncology, with a focus on malignancies that represent health disparities among Hispanics. Throughout my doctoral training, I worked on various research projects that examined the genetic and environmental factors that contribute to gastric and colorectal cancer disparities among Hispanics, which led me to design the present study that combines my expertise in microbiology and gastrointestinal oncology to examine host genetic susceptibility to gut microbiota-driven colorectal cancer (a gene-environment interaction). Colorectal cancer (CRC) is one of the leading causes of cancer death in Puerto Rico and the U.S. More than 60% of CRC patients in the U.S. are diagnosed at more advanced stages, emphasizing the need for CRC prevention and risk stratification strategies, that other than routine screening, are still unavailable. Host genetics and environmental factors, including inflammation and the gut microbiota, are accepted as major contributors to colorectal carcinogenesis. A dynamic balance between the host immune system and the gut microbiota is essential to protect colonic tissues against chronic inflammation, which may lead to CRC. Cytokines maintain the balance between pro- and anti-inflammatory actions. Single nucleotide polymorphisms (SNPs) in the promoter regions of the IL-1?, IL-6 and IL-10 genes, key cytokines that regulate inflammation in the gut, have been reported to alter their expression, increase inflammation, and are associated with CRC. Intestinal inflammation has also been shown to alter the gut microbiota by enriching Gram-negative bacteria, some of which have toxins that may contribute to colorectal carcinogenesis. The main goal of this study is to investigate if SNPs in the promoter regions of the IL-1?, IL-6 and IL-10 genes, key cytokines that regulate inflammation in the gut, increase the risk for colorectal adenomas (CRC precursor lesions) by enriching a subset of toxin-producing gut microbiota (gene-environment interaction). The central hypothesis is that individuals with pro-inflammatory genotypes have increased colonic inflammation that leads to an enrichment of toxin-producing gut microbiota, thereby promoting the carcinogenic process. This study proposes three innovative, hypothesis-driven Specific Aims. Using a case- control study design, Aim 1 & 2 will examine the association between SNPs in key cytokine genes, gut bacteria toxin genes, and colorectal adenomas. Aim 3 will result in the generation of an in vitro enteroid model to study the mechanisms underlying the CRC-promoting host genetic-gut microbiota interactions. The significance of this study is that it will contribute to a better understanding of host genetic susceptibility to gut microbiota- driven CRC (gene-environment interaction) and will be the foundation for the development of host gene- and/or bacterial gene-based CRC prevention and/or risk stratification strategies that will ultimately help reduce CRC incidence and mortality. The protected time provided by this award will be invaluable for the development of my independent research track and for the generation of strong preliminary data for future grant submissions.